The clinical relevance of RAS pathway gene mutations in childhood B-cell acute lymphoblastic leukemia.

Authors

Xiaoyu Chen, Li Gao, Yongping Zhang, Yixin Hu, Jian Pan, Zhiheng Li, Jun Lu, Yizhen Li, Shaoyan Hu

Published in

Annals of hematology. Jul 13, 2026. Epub Jul 13, 2026.

Abstract

Notably, FLT3 and RAS pathway gene mutations represent a significant proportion of childhood B-cell acute lymphoblastic leukemia (B-ALL) cases. Our study explores whether these patients have distinct clinical features and prognostic outcomes.
We retrospectively analyzed 488 pediatric B-ALL cases from the CCCG-ALL-2015 cohort using whole transcriptome sequencing to assess the clinical features of FLT3 mutations, RAS pathway alterations, and their cooperative effects.
192 patients (39.3%) carried at least one RAS pathway alterations, while 76 patients (15.6%) had FLT3 mutations. Strikingly, 6 of 11 NF1-mutated patients harbored concurrent FLT3 mutations. A significant correlation was observed between FLT3 and NF1 mutations (Phi coefficient = 0.16, χ² = 13.0, p < 0.001), NRAS and KRAS mutations (Phi coefficient = 0.19, χ² = 17.12, p < 0.0001), NRAS and PTPN11 (Phi coefficient = 0.138, χ² = 9.54, p = 0.0042). FLT3/NF1 co-mutated patients exhibited a higher frequency of abnormal karyotypes and had significantly poorer overall survival (OS) and event-free survival (EFS) (p < 0.05), particularly when compared to those without KMT2A rearrangements (p = 0.004 and p = 0.003, respectively). Collectively, RAS pathway alterations were not significantly associated with inferior OS or EFS. Multivariable Cox regression analysis confirmed that FLT3/NF1 co‑mutations were independently associated with inferior OS (HR = 12.39, 95% CI: 1.40-109.46, p = 0.024), and multivariable logistic regression analysis showed that they were also independently associated with Day 46 MRD ≥ 0.01% (OR = 9.50, 95% CI: 1.65-54.71, p = 0.01).
Our findings suggest that FLT3/NF1 co-mutations-rather than other RAS pathway mutations, may be associated with adverse outcomes in pediatric B‑ALL, warranting further validation.
The study was conducted with approval from the Institutional Review Board of Children's Hospital of Soochow University (Approval number: 2019KS006).

PMID:
42440143
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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